5-Fluorouracil Floxuridine

Chemotherapeutic agents that have significant cancer response when combined with hyperthermia (up to 43°C) include doxorubicin, melphalan, mitomycin C (MMC), mitoxantrone, gemcitabine, etoposide, and especially the platinum-based agents carboplatin and oxaliplatin (Mohamed et al., 2003 Sugarbaker et al., 2005). Agents that do not work well with hyperthermia include irinotecan, paclitaxel, docetaxel, 5-fluorouracil, and floxuridine (Mohamed et al., 2003 Sugarbaker et al., 2005). 

Fig. 2. Structure of fluorouracil (5-FU) and floxuridine (5-fluoro-2 -deoxyuridine, FdUrd).

In addition to the usual intravenous or oral routes, some anticancer agents have been administered by regional intraarterial perfusion to increase drug delivery to the tumor itself and at the same time diminish systemic toxicity. Thus, patients with metastatic carcinomas of the liver and little or no disease elsewhere (a common occurrence in colorectal cancer) can be treated with a continuous infusion of fluorouracil or floxuridine through a catheter implanted in the hepatic artery. 

Floxuridine (FUDR) is the nucleoside of 5-fluo-rouracil that is readily converted into 5-fluorouracil in vivo. It has similar pharmacological effects but is preferred to 5-fluorouracil for hepatic arterial infusions because it is more extensively metabolized in the liver than 5-fluorouracil, with less systemic toxicity. 

Apart from Ro-28-2653, mentioned above, another important class of pyrimidine antitumor agents is represented by 5-fluorouracil (5-FU) 1035, which shows activity against a variety of different solid tumor types by functioning as an inhibitor of thymidylate synthase (TS) <2005CME2241>. 5-Fluoro-2 -deoxyuridine (FdUrd, floxuridine) 1036 is also widely used <2006JFC(127)303>. 

Fluorouracil and fluorodeoxyuridine (floxuridine) inhibit pyrimidine nucleotide biosynthesis and interfere with the synthesis and actions of nucleic acids. To exert its effect, fluorouracil (5-FU)... 

Fluorouracil and fluorodeoxyuridine (floxuridine) inhibit pyrimidine nucleotide biosynthesis and interfere with the synthesis and actions of nucleic acids. To exert its effect, fluorouracil (5-FU) must first be converted to nucleotide derivatives such as 5-fluorodeoxyuridylate (5-FdUMP). Similarly, floxuridine (FUdR) is also converted to FdUMP by the following reactions ... 

Fluorouracil is normally given intravenously (Table 55-3) and has a short metabolic half-life on the order of 15 minutes. It is not administered by the oral route because its bioavailability is erratic due to the high levels of the breakdown enzyme dihydropyrimidine dehydrogenase present in the gut mucosa. Floxuridine (5-fluoro-2 -deoxyuridine, FUDR) has an action similar to that of fluorouracil, and it is only used for hepatic artery infusions. A cream incorporating fluorouracil is used topically for treating basal cell cancers of the skin. 

SYNS DEOXYFLUOROURIDINE l-p-d-2 -DEOXYRIBOFURANOSYL-5-FLUOROURACIL FDUR FLOXURIDIN FLOXURIDINE FLUORODEOXY-URIDINE p-5-FLUORO-2 -DEOXYURIDINE 5-FLUORODEOXYURIDINE 5-FLUORO-2-DEOXY-URIDINE 5-FLUORO-2 -DEOXYURIDINE 5-FLUOROURACIL DEOXYRIBOSIDE 5-FLUORO-URACIL-2 -DE0XYRIB0SIDE FLUORURIDINE DEOXYRIBOSE FUDR 5-FUDR NSC-27640 RO 5-0360... 

Of 57 consecutive patients treated with implanted hepatic arterial infusion pumps with a regimen of alternating floxuridine (0.1 mg/kg/day for 7 days) followed by a weekly pump bolus of 5-fluorouracil (15 mg/kg for 3 weeks), two developed biliary sclerosis and 12 had mild transient liver function abnormalities (103). The liver alone or in combination with another area was the site of first progression of disease in 40 patients. 

Folate analogs Methotrexate Pemetrexed Trimetrexate Purine analogs Cladribine Fludarabine Mercaptopurine Pentostatin Thioguanine Pyrimidine analogs Capecitabine Cytarabine Floxuridine Fluorouracil Gemcitabine... 

Clinically important, potentially hazardous interactions with acenocoumarol, alfuzosin, aminophylline, anisindione, anticoagulants, buprenorphine, butorphanol, caffeine, carmustine, dobazam, cocoa, dicumarol, dofetilide, duloxetine, epirubicin, eszopiclone, fentanyl, floxuridine, fluorouracil, galantamine, gliclazide, hydromorphone, itraconazole, ketoconazole, lidocaine, meptazinol, midazolam, mizolastine, modobemide, morphine, narcotic analgesics, oxprenolol, oxycodone, pentazocine, phenytoin, posaconazole, prednisone, propranolol, sufentanil, tolazoline, warfarin, xanthines, zaleplon, zofenopril, zolmitriptan, zolpidem... 

Because approximately two-thirds of patients who undergo resection of hepatic metastases will have disease recurrence, adjuvant systemic and hepatic arterial infusion chemotherapy have been studied in an attempt to improve long-term outcomes. A randomized trial that compared 6 months of hepatic floxuridine and dexamethasone plus TV fluorouracil with leucovorin to TV fluorouracil with leucov-orin alone following resection of hepatic metastases in 156 patients showed improved 2-year DPS (86% vs. 72%) and hepatic recurrence-free survival at 2 years (90% vs. 60%) with the combined therapy. Many practitioners offer adjuvant chemotherapy to select patients following potentially curative hepatic resection, but further studies, especially those involving more active agents, are needed to determine an optimal treatment regimen. ... 

The pharmacokinetic properties of floxuridine in particular provide for rapid systemic clearance and high liver drug extraction (94% to 99%). Fluorouracil has a much lower extraction rate, but is also used frequently. Floxuridine is typically administered as a continuous 24-hour infusion at a dose of 0.1 to 0.3 mg/kg per day for a total of 14 days. This is in contrast to a comparable IV dose equal to 0.125 mg/kg per day. Heparin, in amounts up to 50,000 units per... 

Regional HAI can be accomplished using a hepatic arterial port, a totally implantable pump, or a percutaneously placed catheter into the hepatic artery that is connected to an external pump. The volume of drug required to administer floxuridine can be contained within an implantable pump, whereas fluorouracil administration generally requires use of an external pump. Implanted infusion pumps are typically loaded with a 2-week volume of chemotherapy that is followed by an infusion of heparinized saline for 2 weeks. Candidates are selected carefully based on documentation of hepatic-only disease, good performance status, and no significant comorbidities or liver anatomic variants. 

In two randomized trials in which HAI floxuridine was compared to systemic fluorouracil plus leucovorin, and treatment crossover was not allowed, the European trial did not detect any treatment difference in progression-free or OS, whereas the CALGB trial showed improved time to hepatic progression (9.8 vs. 7.3 months) and median OS (22.7 vs. 19.8 months) with HAL However, both studies were affected by pump-related delays and complications, and the final analysis of the CALGB study has not been published. ... 

Cytarabine Floxuridine (Ara-C) Fludarabine phosphate (5-Fluorodeoxyuridine) Fluorouracil (F-ara-A fludara)... 

Fluorouracil (5-FU) requires enzymatic conversion to the nucleotide (ribosylation and phosphorylation) in order to exert its cytotoxic activity. Several routes are available for the formation of floxuridine monophosphate (FUMP). 5-FU may be converted to fluorouridine by uridine phos-phorylase and then to FUMP by uridine kinase, or it may react directly with 5-phosphoribosyl-l-pyrophosphate (PRPP), in a reaction catalyzed by orotate phosphoribosyl transferase, to form FUMP. Many metabolic pathways are available to FUMP. As the triphosphate FUTP, it may be incorporated into RNA. An alternative reaction sequence... 

FIGURE 51-5 Activation pathways for 5 fluorouracil (5-FU) and 5-floxuridine (FUR). FUDP, floxuridine diphosphate FUMP, floxuridine monophosphate FUTP, floxuridine triphosphate FUdR, fluorodeoxyuridine FdUDP fluorodeoxyuridine diphosphate FdUMP fluorodeoxyuridine monophosphate FdUTP fluorodeoxyuridine triphosphate PRPP 5-phosphoribosyl-1 -pyrophosphate. 

An alternative activation pathway involves the thymidine phosphorylase catalysed conversion of 1 to Floxuridine (FUDR, 4), which is then phosphorylated by thymidine kinase to give 19. The metabolite of 1 - Floxuridine - is itself used as an anti-cancer agent [9]. It was launched in 1970 by Hospira hic [5]. Upon rapid injection, most of Hoxuiidine is catabolized to Fluorouracil hence similar effects on the organism are obtained in this case. On the contrary, when 4 is slowly administered into the arterial blood, it is mostly transformed to 19 thus toxic effects are diminished comparing to 1 [10]. 

Early synthesis of Floxuridine commenced from Fluorouracil (1) which was transformed into its mercury salt 28 and then allowed to react with 2-deoxy-D-ribofuranosyl chloride derivative 29 (Scheme 4) [18]. The product 30 was subjected to alkaline hydrolysis to give Floxuridine (4). 

As in the case of Fluorouracil, newer syntheses of Floxuridine relied on direct fluorination of uracil derivatives. Fluorination of uridine 31 was done using fluorine [19], acetyl fluoride [20], and CF3OF [21], The latter reagent gave good but still moderate yield of the product 4 (47 %). The use of a two-step reaction sequence, Le. fluorination of diacetoxy derivative 32 and hydrolysis, improved the yield of 4 to 82 % over two steps [21, 22],... 

Apart from Floxuridine, Fluorouracil and its pro-drugs, there are two additional examples of anti-cancer agents which also act as antimetaboUtes and have reached clinical development phase, i.e. both Trifluridine (7) (as a component of TAS-102) and FTC-092 (74) (Fig. 4) were developed by Taiho Pharmaceutical. These... 

Antimetabolites 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), Capecitabine, Floxuridine, Fludarabine, Gemcitabine, Hydroxyurea, Methotrexate, Pentostatin, Thioguanine ... 

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